p53 mutations and clonality in vulvar carcinomas and squamous hyperplasias: Evidence suggesting that squamous hyperplasias do not serve as direct precursors of human papillomavirus-negative vulvar carcinomas

Kim, Young‐Tak; Thomas, Neena F; Kessis, Theodore D.; Wilkinson, Edward J.; Hedrick, Lora; Cho, Kathleen R.

doi:10.1016/s0046-8177(96)90113-6

Cited by 72 publications

(49 citation statements)

References 20 publications

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“…12,13,15,54 The reasons for this apparent lack of correlation in some cases may be multifold: (1) the presence of mixed morphologic features in the different areas of the tumor, resulting in imprecise classification (eg presence of keratin pearls in basaloid carcinoma, presence of pseudokoilocytes or inconspicuous keratin pearls in keratinizing carcinoma); (2) detection of 'passenger HPV' resulting in non-correlating positive result of HPV detection and negative result of p16 INK4a staining; (3) failure of HPV DNA amplification resulting in noncorrelating negative result of HPV detection and positive result of p16 INK4a staining; (4) additionally, a recent study from our laboratory showed that false-positive interpretive error of 'blush' p16 INK4a immunostaining could result in a lack of correlation with detection of high oncogenic risk HPVs in cervical mucosa. 55 The overlapping histologic features in different tumor subtypes were analyzed in detail in a recent study by Santos et al 13 In the series of vulvar carcinomas described by Santos et al, keratin pearls were identified in over a half of basaloid carcinomas and in all warty and keratinizing carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…19 Overall, however, p53 gene mutation is an infrequent and rather late event in vulvar carcinogenesis. 11,15,20 As reviewed by Nindl et al, 21 there is evidence supporting a role for cutaneous HPV types belonging to the beta-genus (betaPVs) ( Table 1) in the pathogenesis of non-melanoma skin cancer. Originally, betaPVs have been found in benign and malignant skin lesions from patients with a rare hereditary disease, epidermodysplasia verruciformis.…”

Section: Ink4amentioning

confidence: 98%

“…Although patients with lichen sclerosus have an average 4.5% cumulative risk of vulvar squamous cell carcinomas (reviewed in Carlson 1998, Table 6), 14 neither lichen sclerosus nor squamous cell hyperplasia are universally accepted to be premalignant lesions. 1,14,15 Differentiated VIN or VIN simplex is recognized as an immediate precursor of invasive keratinizing squamous cell carcinomas in the vulva. 1,16,17 Since differentiated VIN is almost invariably seen in association with squamous cell hyperplasia and lichen sclerosus, it is thought to represent a histologically distinct phase of malignant transformation in a non-neoplastic epithelial disorder, such as squamous cell hyperplasia or lichen sclerosus.…”

Section: Ink4amentioning

confidence: 99%

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Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

2008

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Two independent pathways of vulvar carcinogenesis have currently been identified, one related to infection with mucosal human papillomaviruses (HPVs) and a second related to chronic inflammatory or autoimmune processes. The goal of the study was to examine a possible role of cutaneous HPVs from the beta genus in vulvar carcinogenesis and to evaluate the distribution of intratypic variants of HPV 16 in HPV 16-positive vulvar cancer. Consecutive cases of vulvar carcinoma were retrieved from the files and included the following histologic subtypes: keratinizing (n ¼ 21), basaloid (n ¼ 7), warty (n ¼ 1), mixed basaloid-warty (n ¼ 4), verrucous (n ¼ 4), keratoacanthoma (n ¼ 1), basal cell carcinoma (n ¼ 1). All tumors were microdissected and tested for 25 beta HPV types and 25 mucosal HPV types. Cases identified as positive for HPV 16 were further tested for intratypic variants. All cases were immunostained for p16 INK4a . Beta HPVs were not detected in any of the tumor cases. Mucosal HPVs were detected in all but one basaloid/warty carcinomas; of these, nine cases (82%) were positive for HPV 16, including five European subtypes, one African subtype, one North American subtype and two indeterminate subtypes. Two of four verrucous carcinomas were positive for HPV 6. Mucosal HPVs were not detected in keratinizing carcinomas, keratoacanthoma and basal cell carcinoma. All cases of basaloid/warty carcinomas, but none of the remaining tumors, overexpressed p16 The pathogenesis of vulvar carcinoma is not entirely understood. Results of epidemiologic, clinicopathologic and virologic studies are in support of two independent pathways of vulvar carcinogenesis, one related to infection with oncogenic mucosal human papillomaviruses (HPVs) and a second related to a chronic inflammatory and/or autoimmune process involving vulvar mucosa and skin. [1][2][3][4][5][6] Vulvar cancers associated with oncogenic mucosal HPVs tend to occur in young women with past history of genital warts, cervical dysplasia and/or immunosuppression. These carcinomas typically belong to basaloid or warty histologic subtypes and develop from a well-characterized in situ lesion, namely, classic vulvar intraepithelial neoplasia grade 3 (VIN3).7 Approximately 80-90% of HPVpositive vulvar cancers are associated with HPV16 and nearly all remaining tumors are positive for HPV18 and HPV33. [4][5][6][8][9][10][11][12][13] Vulvar carcinomas not associated with mucosal HPVs occur in older women. These well-differentiated keratinizing squamous cell carcinomas histologically resemble conventional squamous cell carcinomas occurring in non-genital skin. 4 However, unlike the usual squamous cell carcinomas, vulvar cancers are not arising in the setting of actinic keratosis. In the vulva, these tumors develop in a background of squamous cell hyperplasia, a chronic inflammatory condition, or long-lasting lichen sclerosus, a lesion with strong links to autoimmune diseases. Although patients with lichen sclerosus

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Section: Discussionmentioning

confidence: 99%

Section: Ink4amentioning

confidence: 98%

Section: Ink4amentioning

confidence: 99%

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Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

2008

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“…11 We first wanted to confirm reports that VIN and VSCC are monoclonal conditions. 5,6 In 8/9 samples of VIN not associated with VSCC and in 16/18 informative samples of VSCC associated with VIN, we found this to be the case. Both ourselves 7 and others 9,12,13 have observed frequent LOH events in VIN and VSCC.…”

Section: Discussionmentioning

confidence: 63%

“…This assumption is based on observations that VIN frequently occurs contiguously with VSCC, 1 that VIN and a subgroup of VSCC are associated with similar risk factors (smoking, 2 immunosuppression 3 and HPV infection 2,4 ) and that VIN and VSCC are monoclonal neoplastic conditions. 5,6 Confirmation of this hypothesis is important for gaining insight into the process of vulval carcinogenesis. Furthermore, identifying molecular markers for risk of progression of VIN to VSCC is possible only if molecular evidence is compatible with a common monoclonal origin of the 2 conditions.…”

mentioning

confidence: 98%

Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases

Rosenthal

Ryan

Hopster

et al. 2002

Intl Journal of Cancer

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VIN is thought to be the precursor of some VSCCs because it is monoclonal, frequently occurs contiguously with VSCC and shares similar risk factors with a subgroup of VSCC. There has been no conclusive molecular evidence supporting this assumption. We performed X-chromosome inactivation analysis on 9 cases of lone VIN, 10 cases of VSCC and associated contiguous VIN and 11 cases of VSCC and associated noncontiguous VIN. Eight of the 9 cases of lone VIN appeared to be monoclonal. All 7 informative and monoclonal cases of VIN with contiguous VSCC and 6/9 informative cases of VIN with noncontiguous VSCC showed patterns of X-chromosome inactivation consistent with a common monoclonal origin for both VIN and VSCC. Two of the 9 cases of VIN with noncontiguous VSCC showed X-chromosome inactivation patterns consistent with a separate clonal origin. We performed LOH analysis at 6 chromosomal loci on these samples and 7 cases with lymph node metastases. Identical losses occurred 7 times in VIN and contiguous VSCC (random probability 1.2 ؋ 10 -9 ), twice in VIN and noncontiguous VSCC (random probability 1.5 ؋ 10 -3 ) and 3 times in VSCC and associated metastases (random probability 1.8 ؋ 10 -5 ). Some losses occurring in VSCC did not appear in the contiguous VIN or associated metastases and vice versa. These data provide molecular evidence that VIN is the precursor of VIN-associated VSCC, that multifocal disease may arise via either different clones or a single clone and that continued divergent clonal evolution may occur in vulval neoplasia. © 2002 Wiley-Liss, Inc. Key words: vulval intraepithelial neoplasia; vulval cancer; loss of heterozygosity; X-chromosome inactivation; vulval squamous cell carcinomaVIN has long been thought to be a premalignant condition that may progress to invasive VSCC. This assumption is based on observations that VIN frequently occurs contiguously with VSCC, 1 that VIN and a subgroup of VSCC are associated with similar risk factors (smoking, 2 immunosuppression 3 and HPV infection 2,4 ) and that VIN and VSCC are monoclonal neoplastic conditions. 5,6 Confirmation of this hypothesis is important for gaining insight into the process of vulval carcinogenesis. Furthermore, identifying molecular markers for risk of progression of VIN to VSCC is possible only if molecular evidence is compatible with a common monoclonal origin of the 2 conditions. We first wanted to confirm that VIN is a monoclonal condition. We then wanted to document the patterns of LOH events and X-chromosome inactivation in VSCC samples and contiguous and noncontiguous VIN, to examine whether VIN and VSCC could have arisen from the same clone. Because we had already studied the frequency of LOH at 6 chromosomal loci in lone VIN and VSCC, 7 it was possible to calculate the odds of identical losses occurring by chance in both VSCC and associated VIN. Finally, as primary cancers and their metastases are thought to have the same clonal origin, we compared the number of identical losses occurring in primaries and their metastases with the...

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Clonal analysis of sporadic pancreatic endocrine tumours

et al. 1998

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The clonal composition of 34 benign and malignant sporadic pancreatic endocrine tumours (PETs) of female patients was studied using a sensitive polymerase chain reaction (PCR)‐mediated non‐isotopic clonality analysis, which is based on the inactivation patterns of polymorphic X‐linked genes encoding the androgen receptor (AR) and phosphoglycerate kinase (PGK‐1) proteins. Predigestion of DNA with the methylation‐sensitive restriction endonuclease Hpa II permitted selective PCR amplification of the methylated (uncleaved) allele. Amplification was successful in 27 of 34 samples. Twenty patient samples were heterozygous for the AR microsatellite region or Bst XI polymorphic site of the PGK‐1 gene, permitting analysis of clonality. A monoclonal pattern of X‐chromosome inactivation was found in 7 of 20 PETs (35 per cent), since DNA pretreatment with Hpa II blocked amplification of one of the two AR or PGK‐1 alleles. One additional tumour exhibited an oligoclonal inactivation pattern and two others a loss of heterozygosity (LOH) at the AR locus, indicative of monoclonality. A random pattern of X‐chromosome inactivation and polyclonal cellular composition was observed in the remaining ten PETs (50 per cent). When comparing informative benign and malignant PETs, only 2/7 (29 per cent) benign tumours showed a monoclonal pattern and 8/13 (61 per cent) malignant tumours a monoclonal (5), oligoclonal (1), or LOH (2) pattern. The clonal composition of PETs was not associated with a particular growth pattern, proliferation index or immunohisto‐chemical expression pattern. These findings suggest that PETs might initially represent poly‐/oligoclonal neoplastic lesions which are eventually outgrown by a single, more aggressive cell clone with the potential for invasive growth and metastatic spread. Copyright © 1998 John Wiley & Sons, Ltd.

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p53 mutations and clonality in vulvar carcinomas and squamous hyperplasias: Evidence suggesting that squamous hyperplasias do not serve as direct precursors of human papillomavirus-negative vulvar carcinomas

Cited by 72 publications

References 20 publications

Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma

Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases

Clonal analysis of sporadic pancreatic endocrine tumours

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